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Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis

Author

Listed:
  • Dongdong Wang

    (Nanjing Medical University
    Nanjing Medical University
    Nanjing Medical University)

  • Yanxia Li

    (Nanjing Medical University
    Nanjing Medical University)

  • Hao Yang

    (ShanghaiTech University)

  • Xiaoqi Shen

    (Nanjing Medical University)

  • Xiaolin Shi

    (Nanjing Medical University)

  • Chenyu Li

    (Nanjing Medical University)

  • Yongjing Zhang

    (Nanjing Medical University)

  • Xiaoyu Liu

    (Nanjing Medical University)

  • Bin Jiang

    (Nanjing Medical University)

  • Xudong Zhu

    (Nanjing Medical University)

  • Hanwen Zhang

    (Nanjing Medical University)

  • Xiaoyu Li

    (Nanjing Medical University)

  • Hui Bai

    (Nanjing Medical University)

  • Qing Yang

    (Nanjing Medical University)

  • Wei Gao

    (Nanjing Medical University
    Nanjing Medical University)

  • Fang Bai

    (ShanghaiTech University)

  • Yong Ji

    (Nanjing Medical University
    Nanjing Medical University)

  • Qi Chen

    (Nanjing Medical University
    Nanjing Medical University)

  • Jingjing Ben

    (Nanjing Medical University
    Nanjing Medical University)

Abstract

Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor β-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.

Suggested Citation

  • Dongdong Wang & Yanxia Li & Hao Yang & Xiaoqi Shen & Xiaolin Shi & Chenyu Li & Yongjing Zhang & Xiaoyu Liu & Bin Jiang & Xudong Zhu & Hanwen Zhang & Xiaoyu Li & Hui Bai & Qing Yang & Wei Gao & Fang Ba, 2024. "Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48708-0
    DOI: 10.1038/s41467-024-48708-0
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    as
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